Cystic fibrosis (CF) is caused by genetic mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). Disrupted CFTR function leads to a number of clinical manifestations including intestinal obstruction, pancreatic insufficiency, focal biliary cirrhosis, infertility, and recurrent and chronic airway infections resulting in progressive respiratory disease (Welsh et al., Cystic Fibrosis. In The Metabolic and Molecular Basis of Inherited Disease, Scriver et al. (eds.), New York, McGraw-Hill, 2001; Rowe et al., N. Engl. J. Med. 352:1992-2001, 2005).
In human CF, approximately 10-20% of infants arc born with an intestinal obstruction termed meconium ileus (van der Doef et al., Curr. Gastroenterol. Rep. 13:265-270, 2011). This obstruction, due to failed passage of meconium, most commonly occurs in the distal ileum and proximal colon and requires either conservative or surgical interventions to relieve the obstruction (Rescorla et al., World J. Surg. 17:318-325, 1993; Murshed et al., Eur. J. Pediatr. Surg. 7:275-277, 1997). The exact pathogenesis of meconium ileus remains to be determined, but likely results, in part, from defective CFTR-mediated Cl− and/or HCO3− transport by the intestinal epithelium (Clarke et al., J.O.P. 2:263-267, 2001; Harmon et al., Nat. Med. 16:313-318, 2010; Garcia et al., J. Clin. Invest. 119:2613-2622, 2009).
In order to better understand the pathogenesis of CF, CF animal models have been developed including CF mice and more recently CF pigs and ferrets (Grubb et al., Physiol. Rev. 79:S193-214, 1999; Rogers et al., Science 321:1837-1841, 2008; Sun et al., J. Clin. Invest. 120:3149-3160, 2010). A clinical feature of these animal models is the presence of intestinal disease (Grubb et al, Am. J. Physiol. 273:C21-29, 1997; Sun et al., J. Clin. Invest. 120:3149-3160, 2010; Rogers et al., Science 321:1837-1841, 2008; Meyerholz et al., Am. J. Pathol. 176:1377-1389, 2010; Ostedgaard et al., Sci. Transl. Med. 3:74ra24, 2011). Most CF mice models have an intestinal phenotype. However, the clinical and histopathological features are more similar to the distal intestinal obstruction syndrome (DIOS) observed in older humans with CF as opposed to meconium ileus in infants with CF. For example, a small fraction of CF mice die from intestinal disease within days after birth, but most mortality occurs at the time of weaning. In addition, the intestinal obstruction seems to result from intestinal mucus accumulation as opposed to a failure to pass meconium at birth as observed in human CF (Oppenheimer et al., Bull. Johns Hopkins Hosp. 111:1-13, 192; Wilschanski et al., J. R. Soc. Med. 91 Suppl. 34:40-49, 1998).
We have recently developed a porcine model of CF (Rogers et al., J. Clin. Invest. 118:1571-1577, 2008; Rogers et al., Science 321:1837-1841, 2008; Ostedgaard et al., Sci. Transl. Med. 3:74ra24, 2011). CF pigs display many of the same features as humans with CF including meconium ileus, exocrine pancreatic destruction, focal biliary cirrhosis, micro-gallbladder, vas deferens abnormalities, and airway disease (Rogers et al., Science 321:1837-1841, 2008; Meyerholz et al., Am. J. Pathol. 176:1377-1389, 2010; Stoltz et al., Sci. Transl. Med. 2:29ra31, 2010; Ostedgaard et al., Sci. Transl. Med. 3:74ra24, 2011; Welsh et al., Cystic Fibrosis. In The Metabolic and Molecular Basis of Inherited Disease, Scriver et al. (eds.), New York, McGraw-Hill, 2001; Rowe et al., N. Engl. J. Med. 352:1992-2001, 2005). In contrast to humans, there is a 100% penetrance of meconium ileus in both CFTR−/− and CFTRΔF508/ΔF508 newborn piglets. Features of the CF pig meconium ileus very closely replicate that observed in humans with CF including obstruction by meconium in the distal bowel, atretic intestinal segments, and microcolon (Meyerholz et al., Am. J. Pathol. 176:1377-1389, 2010; Rogers et al., Science 321:1837-1841, 2008; Ostedgaard et al., Sci. Transl. Med. 3:74ra24, 2011). The meconium ileus in CF pigs is lethal if not corrected within 24-36 hours after birth. Limited attempts at non-surgical correction (gastrograffin enemas) of the intestinal obstruction in CF pigs have been unsuccessful, in part, due to the atretic intestinal segments. Yet, we have been able to surgically correct the meconium ileus in both CFTR−/− and CFTRΔF508/ΔF508 pigs (Rogers et al., Science 321:1837-1841, 2008; Stoltz et al., Sci. Transl. Med. 2:29ra31, 2010; Ostedgaard et al., Sci. Transl. Med. 3:74ra24, 2011). Despite the success of surgical correction of the meconium ileus in CF pigs, the surgical procedure can be associated with morbidity and mortality and is still not feasible in most CF pigs due complications associated with meconium ileus including intestinal atresia and in utero intestinal perforation.